1. Field of the Invention
This invention generally relates to a non-invasive therapeutic ultrasonic system, and more particularly, to a system which is capable of acoustically imaging and heating a certain region to be treated (xe2x80x9cthe treatment regionxe2x80x9d) in target tissue for therapeutic purposes as well as acoustically monitoring the temperature profile of the treatment region. Further, the present invention relates to a method and apparatus for safely treating a region of body tissue using a single transducer and control unit to monitor and image a temperature profile of the tissue, and using the same transducer and control unit to melt a heat-activated, liposome encapsulated medicant disposed within the tissue.
2. Description of the Related Art
The absorption of energy in tissue, for example, in the human body produces an increase in temperature, which can be exploited for therapeutic purposes. The irradiation of ultrasound to the target tissue such as in the human body, which has been successfully used for decades mainly in increasingly sophisticated diagnostic imaging applications, also allows the target tissue to absorb a certain amount of energy. Thus, ultrasound may be used for therapeutic purposes.
Ultrasound encompasses any sound wave whose frequency is above the human hearing limit which is usually approximated at about 20 KHz. Since frequency and wavelength, and therefore resolution, are inversely related, the lowest sound frequency that is commonly used in imaging the human body is around 1 MHz with a constant trend toward higher frequencies in order to obtain better resolution. Weakening of ultrasonic signals increases with frequency in soft tissues.
In addition, ultrasonic energy at frequencies above 1.5 MHZ has an acoustic wavelength less than 1 mm in the human tissue. This energy is easily controlled in beamwidth and depth of penetration, and has a favorable absorption characteristic in the tissue. These aspects allow the energy to be precisely localized such that regions may be selectively heated while sparing overlying tissue structures.
Therefore, one must consider the exchange in benefits in the depth of penetration that must be achieved for a particular application of diagnostic imaging and the highest frequency that can be used. Applications that require deep penetration, such as cardiology and abdominal applications, typically use frequencies in the 2 to 5 MHz range. Others applications Such as ophthalmology and peripheral vascular applications require shallow penetration but high resolution. Frequencies up to around 20 MHz or higher are used for these types of applications.
Ultrasound has significant advantages for therapeutic applications as compared to micro-wave radio-frequency (RF) energy or optical energy (laser light). In contrast with ultrasound, RF energy is characterized by long wavelengths in tissue, with limited to poor control of energy deposition, and high absorption. These aspects of RF energy constrain its therapeutic usage for large superficial areas. On the other hand, the optical energy which is typically emitted from lasers can be precisely controlled in beamwidth, but the opacity and high absorption in tissue also limits its use to surface treatment or invasive procedures. Furthermore, laser and RF energy are emitted from ionizing radiation sources which are typically associated with some risk, unlike acoustic transducers which are typically used for generating ultrasound.
However, in contrast with the diagnostic uses, the therapeutic uses of ultrasound such as hyperthermia and non-invasive surgery have seen relatively little progress due to several technological barriers. The primary impediment has been a lack of the ability to monitor temperature in the treatment region during the therapeutic treatment process.
Specifically, one objective of the therapeutic application of ultrasound is to create a very well-placed thermal gradient in the target tissue to selectively destroy certain regions. For example, the hyperthermia technique typically requires maintaining tissue temperature near about 43 degrees Celsius, while the goal of non-invasive surgery is typically to elevate tissue temperature above and beyond about 55 degrees Celsius. Moreover, during the therapeutic treatment process, the physiological response of the target tissue is directly related to the spatial extent and temporal duration of the heating pattern. Consequently, in order to appropriately perform feedback and control of the therapeutic treatment process for obtaining successful results, it is absolutely essential to monitor the temperature in the target tissue, for example, so as to know whether or not the temperature in the treatment region has been raised to a level that produces a desired therapeutic effect or destruction in the tissue. In addition, it is preferable to know the temperature distribution in the treatment region and its vicinity for enhancing therapeutic effect.
In the conventional technique, the therapeutic ultrasonic system has typically relied upon thermocouple probes for monitoring the temperature in the treatment region and the vicinity thereof. However, the thermocouple probes are highly invasive because they have to be inserted into the region-of-interest. In addition, use of the thermocouple probes has necessarily led to very poor spatial resolution since only a small number of probes could be safely embedded in the region-of-interest. Furthermore, the embedded thermocouple probes are likely to disturb the acoustic propagation in the tissue and typically cause excessive heating at the probe interface during the therapeutic treatment process. This results in an undesirably modified temperature distribution as well as erroneous measurements.
Another factor which has curtailed progress in the therapeutic uses of ultrasound has been the design of the conventional acoustic transducers.
In general, for the therapeutic treatment process, imaging of the treatment region is necessary to determine the location of the treatment region with respect to the acoustic transducers as well as to evaluate progress of the treatment process. Such essential functions of imaging as well as the aforementioned temperature monitoring may be implemented with the same acoustic transducer to be used for therapeutic purposes, since the acoustic transducers can actually produce an image of the region-of-interest by employing well-established imaging techniques such as B-scan imaging. However, the conventional acoustic transducers which are typically employed for therapeutic purposes are acoustically large, often single-element devices having narrow bandwidth in the frequency domain. Although they are designed to efficiently transmit acoustic energy to the target tissue, the conventional acoustic transducers are typically unsuited for imaging of the treatment region and/or monitoring the temperature profile therein. This precludes development and implementation of these vital functions for performing a desirable precise therapeutic treatment process.
Some prior art references teach the use of ultrasound for therapeutic purposes. For example, U.S. Pat. No. 4,757,820 to Itoh discloses an ultrasound therapy system having functions of imaging and heating the target using ultrasound beams for therapeutic purposes. The system disclosed therein, however, does not include temperature monitoring of the target tissue (treatment region).
U.S. Pat. No. 5,370,121 to Reichenberger et al. discloses a method and apparatus for non-invasive measurement of a temperature change in a subject, in particular a living subject, using ultrasound waveforms. The method and apparatus disclosed therein, however, relies on a differential ultrasound image between two successive ultrasound images of the target. In other words, any temperature change is detected as a temperature-induced change in brightness between the two images, which appears in the differential image. Consequently, an actual real-time monitoring of the temperature may be difficult in the disclosed method and apparatus. Moreover, although the method and apparatus can detect changes in the temperature of the target, an absolute value of the target temperature may not be obtained therefrom. In addition, any movement of the target may introduce changes in the differential image, which may cause erroneous results.
Furthermore, although it is not distinctly intended to be applied in the therapeutic treatment process for a target tissue such as in the human body, U.S. Pat. No. 5,360,268 to Hayashi et al. discloses an ultrasonic temperature measuring apparatus in which a temperature of the target medium is calculated using a propagation time of ultrasonic waves which propagated for a predetermined distance in the target medium. The apparatus disclosed therein, however, is mainly described as employing separate ultrasonic elements which respectively function for a transmitter and a receiver of the ultrasonic waves.
While some prior art temperature monitoring techniques exist, see, for example, U.S. Pat. No. 4,807,633 issued to Fry on Feb. 28, 1989, such techniques are complex and have limited applicability. That is, use of such techniques essentially preclude use of the system for purposes of imaging, unless one were to use multiple transducers. In that regard, while two or more physically separated transducers can be used to accomplish imaging and therapy, typically with one configured for imaging and the other for therapy, such a-system is susceptible to the generation of imprecise data and is overly complex and expensive.
Other prior art references have discussed methods for using ultrasound therapy to treat biological tissues. For example, U.S. Pat. No. 5,149,319 issued to Linger discloses a method for heat treating biological tissues which includes administering a therapeutically effective amount of a hyperthermic potentiator to the tissue and then applying ultrasound to heat the tissue to a temperature of at least about 43 degrees C. Although the potentiators disclosed in this method result in making the hyperthermic ultrasound a more selective and more effective therapeutic method for treating tissue, there is no inclusion of a monitoring means to safeguard against potential overheating and its resulting tissue damage. Further, it should be noted that the hyperthermic potentiators are used to increase the acoustic heterogeneity and generate cavitation nuclei in tumors and tissues, and that this cavitation effect can be harmful to the tissue.
Still other patents disclose the use of lipid-coated micro bubbles or liposomes with ultrasound energy to control and enhance the therapeutic effect on the tissue. For example, U.S. Pat. No. 5,215,680 issued to D""Arrigo discloses an embodiment of the invention which utilizes liposomes which have pooled at the tumor site to enhance the known cavitational and heating effects of ultrasound. The D""Arrigo method involves intravenously injecting liposomes into the body such that they pool at a predetermined area which was previously identified by ultrasonic imaging and then intensifying the ultrasound signal to provide a therapeutic heating and/or cavitational effect. This method also fails to provide means for monitoring the temperature of tissue in order to prevent tissue damage that can occur from overheating.
U.S. Pat. No. 5,348,016 issued to Unger discloses the use of contrast agents for ultrasonic imaging which comprise gas filled liposomes. This patent reference also suggests using liposomes as hyperthermic potentiators for ultrasound and as drug delivery vehicles for use with ultrasound. More specifically, another patent issued to Unger et al., U.S. Pat. No. 5,580,575, discloses a therapeutic drug delivery system using gas-filled micro spheres which includes a method for the controlled delivery of therapeutic compounds to a region comprising the steps of (i) administering the gas-filled micro spheres containing a drug into a patient, (ii) monitoring the micro spheres using ultrasound to determine the presence of the micro spheres in the region, and (iii) rupturing the micro spheres using ultrasound to release the drug in that region. Although these references disclose the use of ultrasound therapy with drug containing liposomes to effect the treatment of tissue, these references do not disclose the use of imaging and temperature monitoring functions to facilitate treatment planning and feedback to ensure the safe treatment of the tissue. Further, these references do not disclose heat treatment of the liposomes themselves, nor the use of heat sensitive liposomes.
Thus, it would be advantageous to provide a compact, non-invasive system capable of acoustically performing the therapeutic heating and imaging of the treatment region in a target tissue as well as temperature monitoring in the treatment region with a single acoustic transducer.
Further, the use of drug or medicant containing liposomes to enhance the therapeutic treatment of targeted areas within the body has become preferred for certain types of medical disorders. Accordingly, there is a need for an ultrasound activated therapy system using medicant containing liposomes which incorporates image and temperature monitoring to assure the safe therapeutic treatment of bodily tissue.
In accordance with various aspects of the present invention, a non-invasive therapeutic ultrasonic system is provided, which features a single acoustic transducer and some other subsystems capable of acoustically performing therapeutic heating and imaging of the treatment region as well as acoustically monitoring the temperature profile in the treatment region and the vicinity thereof. Also disclosed herein is a system architecture and associated components as well as algorithms which can be implemented to acoustically achieve the heating, imaging, and temperature monitoring functions. The imaging and monitoring functions allow precise feedback and control of the therapeutic treatment process so that the therapy can be conducted more successfully. In addition, because a single transducer is utilized, perfect correspondence is obtained; that is, image artifacts and/or imprecise registration difficulties yielded through use of multiple transducers can be avoided.
A novel acoustic transducer disclosed herein is capable of generating high acoustic power for the therapeutic treatment process, while at the same time providing a good imaging function. Specifically, in order to obtain good lateral resolution in the imaging process, the acoustic transducer of the present invention is preferably divided into an array of sub-elements each processing acoustic waves with a sufficient bandwidth for good axial resolution in the imaging process.
These imaging requirements are also extended to the acoustic temperature monitoring function of the treatment region. In accordance with various aspects of the present invention, an acoustic temperature measurement subsystem disclosed herein is capable of non-invasively mapping the temperature distribution or profile in the target tissue in real-time. This feature is accomplished by measuring the time-of-flight and amplitude data of acoustic pulses through the region-of-interest while exploiting the temperature dependence of the speed of sound and acoustic attenuation in the target tissue. The acoustic nature of this process allows the same acoustic transducer which is used for the imaging and therapy functions to be used for the real-time temperature monitoring function. Alternatively, the use of multiple acoustic transducers allows the temperature mapping to be conducted with a higher spatial resolution. The valuable information gathered on the temperature in the target tissue can be used to achieve precise control of the spatial distribution of heating, provide detailed knowledge of the heating duration, and provide quantitative temperature data during the therapeutic treatment process, which has not been previously possible in the conventional art.
In accordance with another aspect of the present invention, a method and apparatus is provided for the safe delivery of medicants within the body using ultrasonic energy. Further, an ultrasound-activated therapy system is provided which utilizes thermally-sensitive liposomes that dissolve upon heating with ultrasound, thereby releasing any drugs or medicants contained within the liposomes at predetermined temperatures into the body for therapeutic treatment. In addition, a method and apparatus is provided for delivering medicant containing liposomes within bodily tissue using ultrasound which incorporate image and temperature monitoring means to assure the proper delivery of the medicant and the safe therapeutic treatment of bodily tissue. Still further, an apparatus is provided for safely delivering a medicant to a region of body tissue which utilizes a single or multiple transducer for monitoring a temperature profile of the tissue region and heating a thermosensitive medicant containing liposome contained in the tissue region.
Additionally, an efficient method and apparatus is provided for safely delivering a medicant to a tissue region which utilizes a single transducer for imaging, temperature monitoring and therapy.
The aspect of the invention directed toward a method for safely delivering a medicant to a tissue region includes the steps of administering a thermosensitive liposome encapsulated medicant to a region of tissue in a body, locating the tissue region using ultrasound imaging, applying ultrasound therapy to heat the tissue region, monitoring the temperature of the tissue region using ultrasound imaging to create a temperature profile, and alternating application of ultrasound imaging and ultrasound therapy until a temperature threshold is reached. The temperature of the tissue region is continuously determined to generate a temperature profile. The temperature profile is continuously and ultrasonically controlled by heating the tissue region to a temperature less than 44 degrees C. and greater than the melt temperature of the liposome. The melt temperature of the liposome is greater than the body temperature of the body including the tissue region. The xe2x80x9cmelt temperaturexe2x80x9d is defined as the temperature where the liposome undergoes phase transition from a crystalline to a liquid or gel.
Preferably, the tissue region is heated to a temperature of about 40-43 degrees C. Typically, the body-temperature is about 37-38 degrees C. The recitation xe2x80x9caboutxe2x80x9d is intended to include temperatures proximate to the recited point or range of temperatures; whereby the present invention would operate in an equivalent manner to one of ordinary skill in the art, or such proximate temperatures would be interchangeable with the recited temperature to one of ordinary skill in the art. Moreover, the melt temperature of the liposome is very sensitive having a variance of about plus or minus 0.5 degrees C., e.g., between 0.1 degrees C. and 0.9 degrees C.
Preferably, the medicant is a therapeutic drug, a reagent, or a bioactive compound.
In addition, the medicant can also be one or more medicants, such as, for example, two different liposomes. Once the liposome melts, it may act as a carrier across cell membranes.
The aspect of the invention directed toward an apparatus for safely delivering a medicant to a tissue region includes means for continuously determining a temperature profile of the tissue region, ultrasonic means for continuously monitoring the temperature of the tissue region and heating a thermosensitive liposome encapsulated medicant located within the tissue region, and means for driving the monitoring and heating means.
The monitoring and heating means are preferably a single transducer that is capable of heating the tissue region to a temperature greater than the melt temperature of the liposome which is greater than the body temperature of the body containing the tissue region. The transducer heats the tissue region with high spatial resolution. The apparatus may also include means for displaying the temperature profile. The means for displaying the temperature profile may be a visual display terminal. Further, the means for continuously determining the temperature profile of the tissue region may be a control unit. The means for driving the transducer may also be the control unit.